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The Role of Platelets in Blood Coagulation During Thrombus Formation in Flow Alen Tosenberger, Fazly Ataullakhanov, Nikolai Bessonov, Mikhail A

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The role of platelets in blood coagulation during thrombus formation in flow Alen Tosenberger, Fazly Ataullakhanov, Nikolai Bessonov, Mikhail A. Panteleev, Alexey Tokarev, Vitaly Volpert To cite this version: Alen Tosenberger, Fazly Ataullakhanov, Nikolai Bessonov, Mikhail A. Panteleev, Alexey Tokarev, et al.. The role of platelets in blood coagulation during thrombus formation in flow. 2012. hal- 00729046v2 HAL Id: hal-00729046 https://hal.archives-ouvertes.fr/hal-00729046v2 Preprint submitted on 13 Sep 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. The role of platelets in blood coagulation during thrombus formation in flow A. Tosenberger1;2, F. Ataullakhanov3;4;5;6, N. Bessonov7, M. Panteleev3;4;5;6 A. Tokarev3;4, V. Volpert1;2;8 1 Institut Camille Jordan, UMR 5208 CNRS, University Lyon 1 69622 Villeurbanne, France 2 INRIA Team Dracula, INRIA Antenne Lyon la Doua 69603 Villeurbanne, France 3 National Research Center for Haematology Ministry of Health and Social Development of Russian Federation Russia, 125167, Moscow, Novii Zykovskii pr., 4a 4 Federal Research and Clinical Centre of Paediatric Haematology, Oncology and Immunology Ministry of Health and Social Development of Russian Federation Russia, 117198, Moscow, Samori Marshela str., 1 5 Faculty of Physics, M. V. Lomonosov Moscow State University Russia, 119991, Moscow, GSP-1, 1-2 Leninskiye Gory 6 Center for Theoretical Problems of Physicochemical Pharmacology Russian Academy of Sciences, Russia, 119991, Moscow, Kosygina str., 4 7 Institute of Mechanical Engineering Problems, 199178 Saint Petersburg, Russia 8 European Institute of Systems Biology and Medicine, 69007 Lyon, France Abstract. Hemostatic plug covering the injury site (or a thrombus in the pathological case) is formed due to the complex interaction of aggregating platelets with biochemical reactions in plasma that participate in blood coagulation. The mechanisms that control clot growth and which lead to growth arrest are not yet completely understood. We model them with numerical simulations based on a hybrid DPD-PDE model. Dissipative particle dynamics (DPD) is used to model plasma flow with platelets while fibrin concentration is described by a simplified reaction-diffusion-convection equation. The model takes into account consecutive stages of clot growth. First, a platelet is weakly connected to the clot and after some time this connection becomes stronger due to other surface receptors involved in platelet adhesion. At the same time, the fibrin network is formed inside the clot. This becomes possible because flow does not penetrate the clot and cannot wash out the reactants participating in blood coagulation. Platelets covered by the fibrin network cannot attach new platelets. Modelling shows that the growth of a hemostatic 1 plug can stop as a result of its exterior part being removed by the flow thus exposing its non-adhesive core to the flow. 1 Introduction Hemostasis is a protective physiological mechanism that functions to stop bleeding upon vascular injury by sealing the wound with aggregates of specialized blood cells, platelets, and with gelatinous fibrin clots. Disorders of this system are the leading immediate cause of mortality and morbidity in the modern society. The most prominent of them is thrombosis, the intravascular formation of clots that obstruct blood flow in the vessels. Life-threatening thrombus formation is an ubiquitous complication or even cause of numerous diseases and conditions such as atherosclerosis, trauma, stroke, infarction, cancer, sepsis, surgery and others. To provide only one example, 70% of sudden cardiac deaths are due to thrombo- sis [1]; and the sudden cardiac deaths annually kill approximately 400 000 people in the United States only [2]. Development of thrombosis diagnostics and antithrombotic therapy is hampered by the incredible complexity of the hemostatic system comprising thousands of biochemical reactions of coagulation and platelet signaling that occur in the presence of spatial heterogeneity, cell reorganization and blood flow. The most promising pathway to resolving this problem is systems biology { a novel multidisciplinary science aimed at quantitative analysis and understanding of complex biological systems with the help of high- throughput experimental methods and computational modelling approaches. During the last 20 years, the hemostasis system was a subject of intense interest in this field; reviews are available that describe these theoretical studies of blood coagulation [3,4] and platelet- dependent hemostasis and thrombosis [4,5,6]. In recent years, computational modeling of coagulation has become a very widely used tool for investigation of the mechanisms of drug action, optimization of therapy, analysis of drug-drug interaction at early stages (e.g. see recent examples for direct factor Xa inhibitors, novel anti-TFPI aptamer and recombinant activated factor VIII [7,8,9]). However, numerous problems remain. There is currently no mathematical model that could adequately account for all innumerable aspects of thrombosis and hemostasis; even the best ones usually use very unreliable assumptions about platelets, biochemistry and hydrodynamics. The solution of these problems requires a close cooper- ation between specialists in the hemostasis field and those in computational mathematics. This paper provides a brief review of the field from a biological and medical point of view, followed by a computational analysis of the problem of thrombus formation using dissipative particle dynamics methods. 2 2 Platelets, flow, and blood coagulation Hemostasis is a protective physiological mechanism that functions to stop hemorrhage upon vascular injury. The two principal components of hemostasis are: i) platelets, specialized cells that adhere to the damaged tissue and form a primary plug reducing blood loss (Figure 1A); ii) blood coagulation, a complex reaction network that turns fluid plasma into a solid fibrin gel to completely seal the wound (Figure 1B). Maintaining the delicate balance between the fluid and the solid states of blood is not simple, and a lion's share among the causes of mortality and morbidity in the modern society belongs to hemostatic disorders. The leading one is thrombosis, intravascular formation of platelet-fibrin clots that obstruct blood flow in the vessels. The major obstruction for prevention and treatment of thrombosis is insufficient knowledge of its regulation mechanisms. Platelet aggregation and blood coagulation are extremely complex processes. The attachment of platelets and their accumulation into a thrombus is regulated by mechanical interactions with erythrocytes and the vessel wall, by numerous chemical agents such as thrombin, or ADP, or prostaglandins, or collagen, as well as by an enormous network of intracellular signaling. Blood coagulation is only marginally simpler, including some fifty proteins that interact with each other and with blood or vascular cells in approximately two hundred reactions in the presence of flow and diffusion. Figure 1: Two components of hemostasis. (A) Electron microphotograph of blood platelets [10]. Platelets are small discoid anucleate cells able to undergo activation in case of vascular damage to form hemostatic plugs or pathological thrombi. (B) Main reactions of blood coagulation [11], a reaction cascade that is initiated by tissue factor exposure at the site of damage and produces fibrin, which polymerizes to create a gelatinous clot. Although extensive research during the last decades identified many key players in the hemo- static system, the regulation of hemostasis and thrombosis remains poorly understood. It is extremely difficult to relate a protein or a reaction in such a complex system to the func- tioning of the system as a whole. The most crucial unresolved problem is the very difference 3 between hemostasis and thrombosis. All existing anticoagulants cannot tell them apart and target indiscriminately (that is why it is impossible to prevent coronary artery thrombosis simply by putting all persons in high risk groups on anticoagulation therapy: the possibility of death from external bleeding or a cerebral hemorrhage would become too high). If we knew these mechanisms, it would be possible to target them specifically in order to inhibit intravascular thrombi and prevent blood vessel occlusion while leaving the hemostatic func- tions relatively intact. The most advanced and powerful pathway to decomposing complex systems in systems biology is developing a comprehensive mathematical model and then subjecting it to a sensitivity analysis in a sort of "middle-out" approach; an example of modular decomposition for the blood coagulation cascade can be found in [11]. The most important problem that is hampering the application of this solution is that thrombosis and hemostasis cannot be completely understood without combining all three essential elements: platelets, coagulation, and flow. By forming aggregates, blood platelets build hemostatic plugs and thrombi. This process cannot proceed without flow,
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